Pharmacokinetics and tolerability of inhaled levodopa from a new dry-powder inhaler in patients with Parkinson’s disease

Abstract

Background: Inhaled levodopa may quickly resolve off periods in Parkinson’s disease. Our aim was to determine the pharmacokinetics and tolerability of a new levodopa dry-powder inhaler. Methods: A single-centre, single-ascending, single-dose–response study was performed. Over three visits, eight Parkinson’s disease patients (not in the ‘off state’) received by inhalation 30 mg or 60 mg levodopa, or their regular oral levodopa. Maximum levodopa plasma concentration ( C max ), time to maximum plasma concentration (T max ) and area under the concentration time curve 0–180 min were determined. Spirometry was performed three times at each visit. Results: After inhalation, levodopa T max occurred within 15 min in all participants, whereas after oral administration, T max ranged from 20 min to 90 min. The bioavailability of inhaled levodopa without carboxylase inhibitor was 53% relative to oral levodopa with carboxylase inhibitor. No change in lung-function parameters was observed and none of the patients experienced cough or dyspnoea. No correlation was observed between inhalation parameters and levodopa pharmacokinetic parameters. Conclusion: Inhaled levodopa is well tolerated, absorbed faster than oral levodopa, and can be robustly administered over a range of inhalation flow profiles. It therefore appears suitable for the treatment of off periods in Parkinson’s disease.

Intrinsic Auricular Muscle Zone Stimulation Improves Walking Parameters of Parkinson's Patients Faster Than Levodopa in the Motion Capture Analysis: A Pilot Study

“…Oral medications have a latency of up to 90 min to demonstrate symptomatic relief in pace-related gait parameters in PD, and new therapeutic approaches have been tried to overcome this off period of oral medications (28,29). Inhaler levodopa is one of the approaches to overcome this off period and has been shown to have a faster onset compared to oral medications for PD (28,29). However, such inhaler options do not eliminate the long-term risks of levodopa usage and the resulting narrow therapeutic window with increased side effects, including dyskinesia (1)(2)(3).…”

“…Compared to the sole-medication group, the sole-stimulation group demonstrated not only a significant effect but also a faster onset. Oral medications have a latency of up to 90 min to demonstrate symptomatic relief in pace-related gait parameters in PD, and new therapeutic approaches have been tried to overcome this off period of oral medications ( 28 , 29 ). Inhaler levodopa is one of the approaches to overcome this off period and has been shown to have a faster onset compared to oral medications for PD ( 28 , 29 ).…”

Optimizing Spray-Dried Porous Particles for High Dose Delivery with a Portable Dry Powder Inhaler

“…In this example, Luinstra et al [ 89 , 90 ] co-milled levodopa with 2% w / w leucine. Thirty milligrams of the coated drug particles was loaded into the Cyclops single-use disposable DPI (packing density = 85.7 mg/mL) and the systemic pharmacokinetics (i.e., the target for CNS delivery) and tolerability of inhaled levodopa was assessed in eight patients with Parkinson’s disease.…”

Optimizing Spray-Dried Porous Particles for High Dose Delivery with a Portable Dry Powder Inhaler

“…In this example, Luinstra et al [90,91] co-milled levodopa with 2% w/w leucine. Thirty milligrams of the coated drug particles were loaded into the Cyclops single-use disposable DPI (packing density = 85.7 mg/mL), and the systemic pharmacokinetics (i.e., the target for CNS delivery) and tolerability of inhaled levodopa was assessed in eight patients with Parkinson's disease.…”

“…Based on non-compendial laser diffraction testing in the absence of a throat, it was claimed that these devices achieve high fine particle fractions and low throat deposition in vivo [88,90]. Pharmacokinetic studies with tobramycin in bronchiectasis patients [89] and levodopa in Parkinson's patients [91] suggest that lung delivery may be significantly less than suggested by these in vitro measurements. The dose-normalized systemic Cmax and AUC values observed with the Cyclops-based products are approximately two-fold lower than is observed with TOBI Podhaler and Inbrija (Section 4.1).…”